The clinical, molecular, and therapeutic implications of time from primary diagnosis to brain metastasis in lung and breast cancer patients

Abstract Purpose Lung cancer (LC) and breast cancer (BC) are the most common causes of brain metastases (BMs). Time from primary diagnosis to BM (TPDBM) refers to the time interval between initial LC or BC diagnosis and development of BM. This research aims to identify clinical, molecular, and therapeutic risk factors associated with shorter TPDBM. Methods We retrospectively reviewed all diagnosed LC and BC patients with BM at Harbin Medical University Cancer Hospital from 2016 to 2020. A total of 570 patients with LC brain metastasis (LCBM) and 173 patients with breast cancer brain metastasis (BCBM) patients who met the inclusion criteria were enrolled for further analysis. BM free survival time curves were generated using Kaplan–Meier analyses. Univariate and multivariate Cox regression analyses were applied to identify risk factors associated with earlier development of BM in LC and BC, respectively. Results The median TPDBM was 5.3 months in LC and 44.4 months in BC. In multivariate analysis, clinical stage IV and M1 stage were independent risk factors for early development of LCBM. LC patients who received chemotherapy, targeted therapy, pulmonary radiotherapy, and pulmonary surgery had longer TPDBM. For BC patients, age ≥ 50 years, Ki67 ≥ 0.3, HER2 positive or triple‐negative breast cancer subtype, advanced N stage, and no mastectomy were correlated with shorter TPDBM. Conclusions This single‐institutional study helps identify patients who have a high risk of developing BM early. For these patients, early detection and intervention could have clinical benefits.


| INTRODUCTION
Lung cancer (LC) and breast cancer (BC) have been the most prevalent types of cancer worldwide for decades. 1 LC and BC are also the most common primary tumors that metastasize to the brain, accounting for an average of 45% and 15% of all brain metastases (BMs), respectively. 2In the vast majority of cases, the appearance of BM is a sign of poor prognosis.For instance, only one in four LCBM patients survives beyond 1 year after diagnosis. 3For BCBM, the 1-year survival rate is approximately 20%. 4 Despite advances in targeted therapy and immunotherapy, only a limited number of BM patients benefit from these novel treatment methods. 5Moreover, improvements in primary tumor control and an aging population contribute to the elevated incidence of BM. 6 Therefore, early detection and diagnosis are important in BM management.
Several previous studies focused on exploring risk indicators for BM.As they demonstrated, molecular features are one of the critical factors that affect BM incidence.LC patients with epidermal growth factor receptor (EGFR) mutation 7 and BC patients whose human epidermal growth factor receptor 2 (HER2) is positive 8 tend to develop BM more frequently.Some clinical features, such as the diameter of the primary lung lesion and carcinoembryonic antigen (CEA) concentration, could also serve as independent risk factors for LCBM. 9In addition to the abovementioned factors, the timing of BM, which varies widely in clinical work, deserves attention.In some cases, metastatic tumors are found synchronously with or even before primary cancer. 10This early dissemination is more prevalent in LC and melanoma. 115][16] Early diagnosis and treatment of BM could reduce complications and prolong metastatic survival. 17Hence, it is vital to screen the factors involved in the development of BM.In clinical work, a patient with shorter TPDBM equates to the patient developing BM in the early stage of the primary lesion, and these patients in particular require special attention.A better understanding of the factors that impact TPDBM in LC and BC may contribute to clinical practice and early intervention with treatment.
The purpose of this study was to describe how clinical features, molecular alterations, and therapy-related factors affect TPDBM in patients with LC and BC with the hope of identifying patients at high-risk of shorter TPDBM who would benefit from early screening and intervention.Compared with previous studies, our research covered all BC and LC subtypes and collected detailed information on treatment regimens that were in accordance with current standard management, making this work more instructive for clinical decision-making.

| Patients
This research was ethically approved by the Ethics Committee of Harbin Medical University Cancer Hospital (#KY2021-42) and conducted by the Declaration of Helsinki.We retrospectively reviewed and analyzed all patients who were diagnosed with subsequent BM from LC or BC between 2016 and 2020 at our hospital.During this period, 27,617 patients with LC and 10,449 patients with BC received treatment at our center.Among them, 3202 LC patients and 733 BC patients were also diagnosed with BM.Patients with BM enrolled in this study met the following criteria 1 : original histologic or molecular reports were available to confirm the diagnosis of LC or BC 2 ; pathological diagnosis or radiographic evidence of BM 3 ; generally complete clinical data; and 4 no previous history of other malignancies.Finally, 570 patients with LCBM (Table 1) and 173 patients with BCBM (Table 2) were screened for eligibility.Written informed consent was obtained from all patients.

| LC and BC subtypes
According to the 2021 WHO classification of lung tumors, 18 the pathologic classification of LC includes small

| Tumor-node-metastasis classification
The Tumor-node-metastasis (TNM) classification was performed according to the standard criteria of the 8th TNM staging system. 21T stage refers to invasion into adjacent tissue; N stage refers to regional lymph node involvement, and M stage refers to distant metastases of the primary tumor.

| Univariate and multivariate analysis in LC
Significant risk indicators of shorter TPDBM in all LC patients were screened from the univariate analysis: clinical stage, T2 stage, advanced N stage, M1 stage, chemotherapy, target therapy, pulmonary radiotherapy, and pulmonary surgery (Table 3).In multivariate analysis, clinical stage IV (HR = 2.678, p = 0.007) and M1 stage (HR = 2.678, p = 0.007) at initial diagnosis remained independent risk factors for shorter TPDBM.In contrast, our results indicated that patients who received chemotherapy after surgery (HR = 0.478, p = 0.038), chemotherapy prior to and after surgery (HR = 0.432, p < 0.001), targeted therapy (HR = 0.506, p < 0.001), pulmonary radiotherapy (HR = 0.703, p = 0.002), and pulmonary surgery (HR = 0.351, p = 0.002) developed BM later.Age, sex, pathologic subtype, and T stage were not statistically associated with TPDBM in the final results.The final significant results are shown in the forest plot in Figure 2A.
For LUAD patients, we were curious about whether EGFR mutation alterations would affect TPDBM.Although EGFR mutation was associated with TPDBM in univariate analysis (HR = 0.617, p = 0.001), no significant results were found in multivariate analysis (HR = 0.811, p = 0.309, see Table S1 for details).In addition, clinical stage, metastasis, and surgery were no longer predictive indicators for TPDBM in LUAD.

| DISCUSSION
This retrospective single-center analysis examined various primary cancer characteristics, including age, sex, pathologic subtype, molecular features, clinical stage, TNM stage, and therapeutic methods, that are associated with interval time to the occurrence of BM.This was a large-scale study that focused on TPDBM in all LC and BC subtypes at the same time.Moreover, compared with previous studies, which mainly discussed the impact of pathologic subtype on TPDBM, we also incorporated molecular alterations and detailed treatment modalities into multivariate analysis.Over the past decade, the improvement of comprehensive therapies has prolonged the overall survival of patients with LC and BC.This leads to the high incidence of BM, a common cause of morbidity and mortality.We believe that the present study may help to identify patients who have early development of BM.Early detection and intervention of these high-risk patients are critical and beneficial.
Our results demonstrate that LC has an obviously shorter TPDBM than BC (median 5.3 months vs. 44.0months, p < 0.001).For LC patients, median TPDBM is longest in SCLC (7.5 months), followed by LUSC (5.5 months), other NSCLC subtypes (5.0 months), and LUAD (3.0 months).However, in all LC patients, the pathologic subtype was not an independent predictor for TPDBM in our results.Another study suggested that nonadenocarcinomatous histopathology was a risk factor for the earlier development of BM in NSCLC. 16As previously reported, we also found that the pathologic subtype is an important factor that impacts the development of BCBM.The median TPDBM for luminal A, luminal B, HER2+, and TNBC was 56, 68, 39, and 33.5 months, respectively.In other studies, TNBC also has a short TPDBM, ranging from 14 to 35 months. 15,22,23Cao et al. 22 revealed that TNBC (HR = 3.062, p < 0.001) and HER2+ (HR = 2.639, p = 0.009) were associated with early development of BC.In our multivariate analysis, TNBC (HR = 3.094, p = 0.002) and HER2+ (HR = 2.593, p = 0.028) were still significant risk factors.Studies also indicate that the incidence of BM varies in different primary tumor subtypes.TNBC is more F I G U R E 1 Kaplan-Meier estimates for BM-free survival.BMfree survival curve for (A) LC and BC, (B) LC subtypes, and (C) BC subtypes.BC, breast cancer; BM, brain metastasis; HER2, human epidermal growth factor receptor 2; LC, lung cancer; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; NSCLC, non-small-cell lung cancer; TNBC, triple-negative breast cancer; TPDBM, time from primary diagnosis to BM. likely to develop BM than the other types 24 and EGFR mutation NSCLC has a higher incidence of BM than EGFR wild-type NSCLC. 25Our research focused on the time course of BM progression, and LC and BC patients without BM were excluded.Therefore, we did not compare the variance in BM incidence in different cancer subtypes.In addition, we investigated the impact of various key molecules on the interval time to BM.The molecular targeted approach has substantially changed the standards of care treatment of LC in recent years. 26,27Accumulating evidence has shown its effectiveness in improving progression-free survival and overall survival. 28EGFR mutations, KRAS mutations, and ALK rearrangements are the most frequent molecular alterations in NSCLC, particularly in LUAD.EGFR and KRAS mutations in primary LC are associated with prognosis. 29However, we detected that the mutation status of EGFR, KRAS, and ALK had no significant influence on TPDBM (Table S1).These findings are consistent with Smith's research. 16However, a multi-institutional analysis detected a significant correlation between both EGFR and ALK gene alterations and interval time to subsequent BM. 30 In our BCBM patient data, we examined the expression of an important proliferation marker, Ki67, in which ≥0.3 was regarded as a high expression.A high Ki67 index is associated with poor BC prognosis, regardless of the timing of specimen examination (i.e., pre/postoperative examination). 31,32However, whether Ki67 can act as an independent predictive factor in the development of BM remains unclear.Our proportional hazards model indicates that a high level of Ki67 in primary BC correlates strongly with early occurrence of BM (HR = 3.024, p < 0.001), suggesting that a Ki67 index of more than 0.3 could serve as an independent risk factor to predict the development of BM.
Novel treatments for cancer patients, especially targeted therapy and immunotherapy, have developed quickly in recent years. 33,34One advantage of our study is that all selected patients were diagnosed with BM between 2016 and 2020 and treated according to generally accepted management.Therefore, our findings could better reflect the contemporary BCBM and LCBM patient population undergoing current therapeutic procedures than previous studies.This may explain why patients in our cohort had a longer TPDBM than previous studies, in which patients were recruited before 2013. 14,35Novel systemic therapies targeting primary lesions generally improve overall survival and progression-free survival. 1,36The majority of published studies focused solely on NSCLC.They revealed that advanced clinical stage, higher T and N stage, and larger primary tumor volume are potential predictors of TPDBM, [37][38][39] which are similar to our results.However, limited information is known about the impact of different treatment approaches on the interval time to BM.Only a few studies suggest that induction chemotherapy is associated with the development of BM. 16,38 We first demonstrate that therapeutic approaches targeting primary LC, including surgery (p = 0.002), chemotherapy after surgery (p = 0.038), chemotherapy prior to and after surgery (p < 0.001), radiotherapy (p = 0.002), and targeted agents (p < 0.001), delay the occurrence of BM in all LC subtypes.However, among all treatment methods, BC patients could only benefit from mastectomy in terms of TPDBM (p = 0.035).
Several studies have demonstrated the prognostic factors associated with a high risk of BM.In LC, patients with EGFR mutation, larger primary lung lesions, and higher CEA concentration were more likely to have BM. 7,9oung age, ER−, HER2+, tumor size >5 cm, and higher presenting stage are regarded as independent risk factors for BCBM. 8,40,41Our research is a good complementary F I G U R E 2 Forest plot of regression analyses.Forest plot of multivariable regression analyses in LC (A) and BC (B).CI, confidence interval; HR, hazard ratio.for studying the progression of BM.Previous studies can help us to screen out the susceptible population for BM and we further identify the patients who may suffer from early BM.For these high-risk patients, additional adjuvant treatments, early intervention, and more intensive follow-up are needed to prevent BM progression in advance.
The results of the present study could provide some novel references for the clinical management of BM.
In light of our findings that certain clinical, molecular, and therapeutic factors significantly influence the TPDBM, it is imperative to consider prophylactic treatment strategies for high-risk LC and BC patients.Early intervention may prevent or delay the development of BMs, potentially improving patient outcomes.Based on the data, patients with high-risk factors for early BMs should be considered for proactive surveillance and potentially preventative therapy.Additionally, the use of targeted therapies, which have shown efficacy in delaying the TPDBM, should be integrated into the treatment regimen for eligible patients.Furthermore, the implementation of regular MRI scans could aid in the early detection of BMs, allowing for timely intervention.Overall, integrating prophylactic strategies into the standard care protocol requires careful consideration of the patient's overall health, cancer subtype, and risk profile.Collaborative efforts between oncologists, radiologists, and neurologists are essential to tailor the most effective prophylactic treatment plans for these high-risk patient populations.
There are some deficiencies in the present study.First, this is a single-institution analysis, which limits the generalizability and applicability of the findings.More research with a larger number of cases from multiple centers is needed to confirm our results.Additionally, survival time data are not completed, and therefore not analyzed.In the future, we will investigate predictive factors for BM patient survival.

| CONCLUSIONS
With the increase in incidence, BM is an intractable medical problem.The present study identifies the risk factors for early BM development in patients with LC and BC.For these high-risk patients, early interventions are warranted and may lead to clinical benefits.
Main characteristics of LCBM patients.
T A B L E 1 Main characteristics of BCBM patients.
T A B L E 2 Univariate and multivariate analysis of TPDBM in LC.
T A B L E 3 Univariate and multivariate analysis of TPDBM in BC.